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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Antagonists of Growth Hormone-Releasing Hormone in Oncology

Author(s): Andrew V. Schally and Jozsef L. Varga

Volume 9, Issue 3, 2006

Page: [163 - 170] Pages: 8

DOI: 10.2174/138620706776055449

Price: $65

Abstract

The development of antagonists of growth hormone (GH) - releasing hormone (GH-RH) is reviewed. GH-RH antagonists bind with a high affinity to pituitary receptors for GH-RH and inhibit the release of GH in vitro and in vivo. The main applications of GH-RH antagonists would be for tumor therapy. The antitumor effects of GH-RH antagonists are exerted in part indirectly through the inhibition of the secretion of pituitary GH and the reduction in the levels of hepatic insulin like growth factor (IGF-I). However, principal effects of the GH-RH antagonists are exerted directly on tumors. Antagonists of GH-RH inhibit the proliferation of various cancer cell lines in vitro and suppress in vivo the levels and the expression of mRNA for IGF-I and IGF-II in tumors. In many human cancers, the effects of GH-RH antagonists appear to be due to the blockade of the action of tumoral GH-RH. GH-RH ligand is present in various human cancers indicating that it may be an autocrine/paracrine growth factor. Splice variants (SVs) of GH-RH receptors and pituitary type of GH-RH receptors that might mediate effects of tumoral GH-RH and of GH-RH antagonists were demonstrated in many human cancers. This suggests the presence of a stimulatory loop based on GH-RH and SVs or pituitary type of GHRH receptors in diverse tumors. It was shown that GH-RH antagonists inhibited the growth of various human cancer lines xenografted into nude mice including mammary, ovarian, endometrial and prostate cancers, small cell lung carcinomas (SCLC) and non-SCLC, renal, pancreatic, gastric and colorectal carcinomas, malignant gliomas, osteosarcomas and Non- Hodgkins lymphomas. Further development of GH-RH antagonists should lead to potential therapeutic agents for various cancers.

Keywords: GH-RH, GH-RH receptors, receptor splice variants, inhibition of pituitary GH release, antitumor activity, cancer therapy


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